Safety of Ancestral Monovalent BNT162b2, mRNA-1273, and NVX-CoV2373 COVID-19 Vaccines in US Children Aged 6 Months to 17 Years

Key Points Question Were statistical signals detected for health outcomes after ancestral monovalent COVID-19 vaccination in US children aged 6 months to 17 years? Findings In this cohort study of 4 102 106 vaccinated enrollees, 2 outcomes met the statistical threshold for a signal compared with historical rates: myocarditis or pericarditis after BNT162b2 (ages 12-17 years) and seizure after BNT162b2 (ages 2-4 years) and mRNA-1273 (ages 2-5 years) vaccinations. Meaning Near-real-time monitoring detected a previously identified statistical signal for myocarditis or pericarditis and a new statistical signal for seizure; however, these results should be interpreted cautiously because the methods only screened for potential statistical signals and have several limitations.


Unusual Site Thrombosis with Thrombocytopenia [Defined in
Footnote] e 365 days 1-28 days [35] Descriptive Only

Definitions:
• Clean Window is the interval used to define incident outcomes where an individual enters the study cohort only if the health outcome of interest did not occur during that interval.• Risk Window is the interval during which occurrence of the health outcome of interest will be included in the analyses.
• Care Setting: IP refers to inpatient facility claims.OP-ED refers to a subset of outpatient facility claims occurring in the emergency department.OP/PB refers to all outpatient facility claims, and professional/provider claims except those professional/provider claims with a laboratory place of service a Source of the claims-based algorithm: FDA.Appendix 7. Safety AE Codes.https://www.bestinitiative.org/wp-content/uploads/2022/01/C19-Vax-Safety-AESI-Bkgd-Rate-Est-Protocol-Suppl.xlsxb The clean window is the interval prior to vaccination where a patient must not have had the outcome.c References for the duration of these windows could not be located in the literature and are instead based on input from clinicians.d Sequential testing was conducted only when the minimum threshold of observed events was met (at least 3 events).For NVX-CoV2373 (ages 12 to 17 years) and mRNA-1273 (ages 6 to 17 years) sequential testing did not initiate due to not meeting this minimum threshold for any of the outcomes specified above e Both Common thrombosis with thrombocytopenia and Unusual site thrombosis (broad) with thrombocytopenia are combined outcomes consisting of a thrombotic event (made up of other events such as acute myocardial infarction, deep vein thrombosis etc.,) and a thrombocytopenia event (defined in the IP, OP/PB setting).The overall setting definition for each outcome depends on individual setting definitions for each of these components.f Feasibility of sequential testing of certain outcomes in specific age groups was evaluated based on availability of background rates.Guillain a HCPCS: The Healthcare Common Procedure Coding System produced by the Centers for Medicare and Medicaid Services (CMS) [36] CPT: The Current Procedural Terminology codes [36] b CVX: Vaccine administered code set developed and maintained by the Centers for Disease Control and Prevention's (CDC) National Center of Immunization and Respiratory Diseases (NCIRD) [37] c NDC: National Drug Codes used to identify and report drugs using a unique, three-segment number which serves as the Food and Drug Administration's (FDA) identifier for drugs [38] ©

eAppendix. Medical Record Review
Medical record review was conducted for the myocarditis/pericarditis outcome following identification of a statistical signal.Brighton Collaboration case definitions were used to adjudicate cases. 39Records meeting the confirmed or probable Brighton classifications were considered true myocarditis/pericarditis cases for the validation analyses.
Of the 153 cases of myocarditis/pericarditis after COVID-19 vaccination among children aged 12-17 years, medical record review was conducted for a sample of 40 cases whose records could be obtained.Twenty-nine of these cases (72.5%) were confirmed as true cases of myocarditis/pericarditis, of which 27 patients were male, and 19 were hospitalized with a median length of hospital stay of 2 days (interquartile range: 1, 3).The median time from vaccination to presentation of myocarditis/pericarditis event was 3 days (interquartile range: 2, 5).Medical record review and further validation efforts for seizure are currently underway.

a
Combines data for all three data sources: Carelon Research: Data through 3/2023, CVS Health: Data through 2/2023, M et al.JAMA Network Open.

eTable 4. Administrative Codes for COVID-19 Vaccine Administration used in claims and IIS databases HCPCS/CPT a Codes CVX b Codes (IIS- Specific) Manufacturer Name Age Group (years) Vaccine Administration Code NDC c 11 Labeler Product ID (Vial) Dosing Interval
-Barré Syndrome and Hemorrhagic Stroke were sequentially tested in ages <5 years only and Narcolepsy in ages >5 years old only due to lack of estimable background rates in other age groups

eTable 5. Vaccine Dose Counts for Monovalent BNT162b2, mRNA-1273, NVX-CoV2373 COVID-19 Vaccines Administered to the Pediatric Population Across All Data Sources a
Combines Optum data through 4/2023, Carelon Research data through 3/2023, CVS Health data through 2/2023 § Cell sizes 1-10 and cells that can be used to back-calculate small cell sizes were masked for confidentiality 2024 Hu M et al.JAMA Network Open.© 2024 Hu M et al.JAMA Network Open.eTable 6.

Descriptive Summary of Outcomes Included in Descriptive Analysis Only Outcome Brand All Data Sources Carelon Research a CVS Health b Optum c
§ Cell sizes 1-10 and cells that can be used to back-calculate small cell sizes were masked for confidentiality © 2024 Hu M et al.JAMA Network Open.eTable 7.

Background Annual Rate of Seizures Per 100,000 Person-Years by Data Source in Children Aged 2-4 Years and 2-5 Years, 2020 (Baseline), 2019 and 2022 Ages 2-4 years Ages 2-5 years
For all three data sources, this includes background rates data through 12/2019 b For all three data sources, this includes background rates data through 12/2022 © 2024 Hu M et al.JAMA Network Open. a

eTable 8. Sequential Testing Results for the Pediatric Population Receiving BNT162b2 or mRNA-1273 Ancestral Monovalent COVID-19 Vaccines Stratified by Vaccine Dose and Outcome
© 2024 Hu M et al.JAMA Network Open.© 2024 Hu M et al.JAMA Network Open.© 2024 Hu M et al.JAMA Network Open.

or pericarditis (IP, OP, and ED) (1-7 d)
Common site thrombosis with thrombocytopenia is combined with unusual site thrombosis (broad) with thrombocytopenia consisting of a thrombotic event (made up of other events, such as acute myocardial infarction and deep vein thrombosis) and a thrombocytopenia event (defined in the IP, OP, and physician billing setting).The overall setting definition for the outcome depends on individual setting definitions for each of these components.b For these outcome-age combinations, testing occurred in fewer than 3 data sources because 1 or more data source did not have available background rates; for these outcome-age combinations, number of doses are reported for the data sources for which sequential testing data were available.c For the outcome seizure, the number of doses reported in the age groups 6 months to 1 year and 2 to 4 or 5 years corresponds to the total number of doses monitored descriptively in the age groups 6 months to 4 or 5 years; all other statistics from sequential testing (number of outcomes, person-time, and statistical signal status) are reported for the corresponding age stratifications listed in the table above due to availability of background rates for those age strata.Sequential testing ended earlier in the age groups 5 or 6 to 17 years due to limited accrual of new exposures; therefore, the data cuts used are different from the age group 6 months to 4 or 5 years.For the age group 5 or 6 to 17 years, Optum data through April 2023, Carelon Research data through January 2023, and CVS Health data through December 2022 were used.For the age group 6 months to 4 or 5 years, Optum data through January 2023, Carelon Research data through March 2023, and CVS Health data through February 2023 were used.
© 2024 Hu M et al.JAMA Network Open. a © 2024 Hu M et al.JAMA Network Open.